Treatment of hypertriglyceridemia with 2-hydroxypropyl-beta-cyclodextrin

drug development, drug discovery,

Fascinating therapeutic application of cyclodextrins have been published by Beren Therapeutics. Earlier the company already patented the use in the therapy of familial hypercholesterolemia, now they propose using hydroxypropyl-BCD against hypertriglyceridemia.
In the 2nd patent composition and purification is reported of a compounds that has a surprisingly high DS (DS-10 being the main component), which composition is far from the materials used as excipients.

WO2023156970 TREATMENT OF HYPERTRIGLYCERIDEMIA WITH 2-HYDROXYPROPYL-BETA-CYCLODEXTRIN (wipo.int)

US20230265219 COMPOSITIONS OF HYDROXYPROPYL-BETA-CYCLODEXTRIN AND METHODS OF PURIFYING THE SAME (wipo.int)

High-Cholesterol Diet in Combination With Hydroxypropyl-β-Cyclodextrin Induces NASH-Like Disorders in the Liver of Rats

carbohydrates, ,

We are hearing a lot about how the cholesterol complexation ability of certain cyclodextrins, especially hydroxypropyl-beta-CD can be used to treat various diseases, like Alzheimer’s, Niemann Pick type C, atherosclerosis, familial hypercholesterolemia and many more.
But can this be a double-edged sword? This fascinating research suggests that High-Cholesterol Diet in Combination With Hydroxypropylβ-Cyclodextrin Induces NASH-Like Disorders in the Liver of Rats

You can read the full article here!

Long-term administration of intravenous Trappsol® Cyclo™ (HP-β-CD) results in clinical benefits and stabilization or slowing of disease progression in patients with Niemann-Pick disease type C1: Results of an international 48-week Phase I/II trial

carbohydrates, drug development, ,

Long-term administration of intravenous Trappsol® Cyclo™ (HP-β-CD) results in clinical benefits and stabilization or slowing of disease progression in patients with Niemann-Pick disease type C1: Results of an international 48-week Phase I/II trial.
Niemann-Pick disease type C (NPC) is a rare, fatal, pan-ethnic, autosomal recessive lysosomal storage disease characterized by progressive major organ failure and neurodegeneration. Preclinical studies confirmed the critical role of systemically administered hydroxypropyl-β-cyclodextrin (HP-β-CD; Trappsol® Cyclo™) in cholesterol metabolism and homeostasis in peripheral tissues of the body, including the liver, and in the central nervous system (CNS). Herein, the pharmacokinetics (PK), safety, and efficacy of HP-β-CD and biomarkers of NPC were assessed in pediatric and adult patients with NPC1.
Cyclo Therapeutics, Inc. –  Caroline Hastings, Sharon Hrynkow et al

Long-term administration of intravenous Trappsol® Cyclo™ (HP-β-CD) results in clinical benefits and stabilization or slowing of disease progression in patients with Niemann-Pick disease type C1: Results of an international 48-week Phase I/II trial – ScienceDirect

2-Hydroxypropyl-β-cyclodextrin (HPβCD) as a Potential Therapeutic Agent for Breast Cancer

Today's cyclodextrin,

today’s cyclodextrin:
Breast cancer is a global burden with the most severe subtype being triple-negative breast cancer (TNBC). Despite advances in conventional therapies, treatment for TNBC is currently lacking. Interestingly, cholesterol has gained interest as a potential therapeutic target due to cancer cells’ increased reliance on this macromolecule. Treatment with the cholesterol-depletory agent 2-hydroxypropyl-β-cyclodextrin (HPβCD) impeded the growth of cancer cells and further led to cancer cell death, which could be attributed to an altered cellular cholesterol profile following treatment. Furthermore, mice xenograft studies indicated complete eradication of early-stage tumours with no relapse, followed by a remarkable reduction in intermediate- and late-stage tumours, respectively. SFRP1 was identified as a possible molecular target facilitating the therapeutic action of HPβCD. These findings consequently potentiate cholesterol depletion as a novel anticancer strategy to be pursued.

University of the Witwatersrand – Tawanda Ziningav Reubina Wadee, Mandeep Kaur et al

See the full article here

ZyVersa Therapeutics Announces Article Published in Metabolism Pointing to Glomerular Cholesterol Accumulation as Key Factor Exacerbating Renal Injury and Dysfunction in Diabetic Kidney Disease

Today's cyclodextrin,

today’s #cyclodextrin:
ZyVersa Therapeutics Inc. published a press release on the mechanism of action of their lead asset, VAR-200, which is hydroxypropyl-beta-cyclodextrin targeting patients with glomerular diseases (#diabetic #kidneydisease, focal segmental glomerulosclerosis, and Alport Syndrome). VAR-200 was able to reduce renal cholesterol and lipid accumulation that damages the kidneys’ filtration system, to mediate transport of excess cholesterol out of kidney cells passively, and by upregulating cholesterol transporter ABCA1.
Deposition of glomerular cholesterol contributes to structural damage and dysfunction of the kidney’s filtration system in models of type 2 diabetes is consistent with data from VAR 200’s preclinical program. By mediating cholesterol transport out of the glomeruli through passive transport and upregulation of ABCA1 transporters, VAR 200 protected against glomerular injury and fibrosis, and significantly reduced protein spillage into the urine in all three kidney diseases

See more about this topic here:
ABCA1 deficiency-mediated glomerular cholesterol accumulation exacerbates glomerular endothelial injury and dysfunction in diabetic kidney disease

ZyVersa Therapeutics Announces Article Published in Metabolism Pointing to Glomerular Cholesterol Accumulation as Key Factor Exacerbating Renal Injury and Dysfunction in Diabetic Kidney Disease

Hydroxypropyl-β-Cyclodextrin Depletes Membrane Cholesterol and Inhibits SARS-CoV-2 Entry into HEK293T-ACEhi Cells

carbohydrates, , ,

Vaccination has drastically decreased mortality due to coronavirus disease 19 (covid19), but not the rate of acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Alternative strategies, such as inhibition of virus entry by interference with angiotensin-I-converting enzyme 2 (ACE2) receptors could be warranted. Cyclodextrins (CDs) are cyclic oligosaccharides that are able to deplete cholesterol from membrane lipid rafts, causing ACE2 receptors to relocate to areas devoid of lipid rafts. To explore the possibility of reducing SARS-CoV-2 entry, hydroxypropyl-β-cyclodextrin (HPβCD) was tested in a HEK293T-ACE2hi cell line stably overexpressing human ACE2 and Spike-pseudotyped SARS-CoV-2 lentiviral particles. Exposure of HEK293T-ACEhi cells to concentrations of HPβCD starting from 2.5 mM to 10 mM showed a concentration-dependent reduction of approximately 50% of the membrane cholesterol content. In addition, incubation of HEK293T-ACEhi cells with HIV-S-CoV-2 pseudotyped particles in the presence of increasing concentrations of HPβCD (from 0.1 to 10 mM) displayed a concentration-dependent effect on SARS-CoV-2 entry efficiency. These data indicate that HPβCD is a candidate for use as a SARS-CoV-2 prophylactic agent.

Silvia Alboni, Valentina Secco, Bianca Papotti, Antonietta Vilella, Maria Pia Adorni, Francesca Zimetti, Laurent Schaeffer, tascedda fabio, Michele Zoli, Pascal Leblanc, Erica Villa

See the full article here: Hydroxypropyl-β-Cyclodextrin Depletes Membrane Cholesterol and Inhibits SARS-CoV-2 Entry into HEK293T-ACEhi Cells

Molecular Mind Games: The Medicinal Action of Cyclodextrins in Neurodegenerative Diseases

carbohydrates, ,

Cyclodextrins are often used as molecular carriers for small active ingredients in the medicine. Recently, the intrinsic medicinal activity of some of these compounds has been under investigation, mainly related to their ability to interfere with cholesterol and, therefore, prevent and treat cholesterol-related diseases such as cardiovascular disease and neuronal diseases arising from altered cholesterol and lipid metabolism. One of the most promising compounds within the cyclodextrin family is 2-hydroxypropyl-β-cyclodextrin (HPβCD), owing to its superior biocompatibility profile. This work presents the most recent advances in the research and clinical use of HPβCD against Niemann–Pick disease, a congenital condition involving cholesterol accumulation inside lysosomes in brain cells, Alzheimer’s and Parkinson’s. HPβCD plays a complex role in each of these ailments, going beyond the mere sequestering of cholesterol molecules and involving an overall regulation of protein expression that helps restore the normal functioning of the organism.
Fantastic review by Susana Santos Braga form Universidade de Aveiro

See the full article here: Molecular Mind Games: The Medicinal Action of Cyclodextrins in Neurodegenerative Diseases

Grafting of Cyclodextrin to Theranostic Nanoparticles Improves Blood-Brain Barrier Model Crossing

drug delivery,

today’s cyclodextrin:
Core–shell superparamagnetic iron oxide nanoparticles hold great promise as a theranostic platform in biological systems. Antonino Puglisi and coworkers report the biological effect of multifunctional cyclodextrin-appended SPIONs (CySPION) in mutant Npc1-deficient CHO cells compared to their wild-type counterparts. CySPIONs show negligible cytotoxicity while they are strongly endocytosed and localized in the lysosomal compartment. Through their bespoke pH-sensitive chemistry, these nanoparticles release appended monomeric cyclodextrins to mobilize over-accumulated cholesterol and eject it outside the cells. CySPIONs show a high rate of transport across blood–brain barrier models, indicating their promise as a therapeutic approach for cholesterol-impaired diseases affecting the brain.

University of Natural Resources and Life Sciences, Vienna (BOKU): Peter van Oostrum, Erik Reimhult
Università degli Studi di Catania: Noemi Bognanni, Graziella Vecchio
Ege University: Ece Bayir
University of Oxford: Dawn Shepherd, Frances Platt

See the full article here: Grafting of Cyclodextrin to Theranostic Nanoparticles Improves Blood-Brain Barrier Model Crossing

Confocal micrographs of Npc1-deficient CHO after incubation with 0.1 mg/mL FITC-CySPION for 72 h showing co-localization, with Pearson’s coefficient of 0.37, between FITC-CySPION (green) and LysoTracker Deep Red within the lysosomal compartments (red) within the ROI preproduced on the right. The used excitation wavelengths and fluorescence maxima are indicated in the figures. The field of view is 290 × 290 µm2.

We the Scientists: How a Daring Team of Parents and Doctors Forged a New Path for Medicine

carbohydrates,

Behind some science, there are stories to learn as the human side is more important than the professional one. The tale that tells us how hydroxypropyl-beta-cyclodextrin became a drug candidate from an excipient to treat desperate patients suffering in Niemann-Pick type C disease is certainly a story worth telling and reading. A new science book by The Wall Street Journal reporter Amy Dockser Marcus took over a decade to write and includes the journey of the Hempel family trying to save Addi & Cassi’s lives with cyclodextrin (they were the first patients treated with the drug).

Order the book on amazon.com

Disease management to disease modification – removing plaque to undo atherosclerosis

Today's cyclodextrin, ,

You can read a great interview with folks from Cyclarity Therapeutics at Longevity.Technology. Since they are one of the few companies developing tailor-made CDs to tackle a major disease, this is certainly worth attention.
“Cyclarity’s approach to true disease medication, and therefore reversal of age-related disease, without doubt, offers a great deal of promise for investors, for healthcare systems in the US and globally, and most of all for those affected by the atherosclerosis-related disease.
. . . this may be the perfect opportunity for Cyclarity to enter the field, as it is one of the few solutions available that addresses the limiting factors of previous therapies both from a scientific perspective and from a market perspective.”

See the full article here